Stem cells and progenitor cells are immature cells with capacity to divide and develop to form any cell type of the mature system. Hematopoietic stem cells (HSC) are able to produce the cells of the immune system and bone marrow. HSC transplantation (HSCT) is used to restore normal hematopoiesis in a patient to treat various diseases after chemotherapy or radiation. During the last couple of decades, HSCT has become a clinical routine treatment for a variety of conditions including multiple myeloma (MM), non-Hodgkin's lymphoma (NHL) and conditions requiring allograft transplantation. Despite the apparent improvements during recent years, the procedure is still associated with a comparably high rate of morbidity and mortality due to complications and relapse of the underlying disease. There is also a continuous need for improving stem cell sources, cell harvesting procedures, conditioning regimens and immunosuppressive treatment. There are two major kinds of HSCT, either allogenic—with stem cells originating from a compatible healthy donor, or autologous—when stem cells are collected from and later given back to the same patient following high dose chemotherapy/radiotherapy conditioning therapy. In allogenic and particularly autologous HSCT, peripheral blood has today almost completely replaced bone marrow as the source for stem cells. Peripheral blood as cell source is preferred since it involves a less invasive procedure for the donor and engraftment of transplanted cells is faster as compared to using bone marrow as the cell source.
Despite the apparent improvements during recent years, the procedure is still associated with a comparably high rate of morbidity and mortality due to transplantation-related complications (mainly allogenic) and relapse of the underlying disease (mainly autologous). Hence, there is a continuous need for improving stem cell sources, cell harvesting protocols, conditioning regimens and immunosuppressive treatment.
Today, stem cells are mobilized to peripheral blood by treatment of the donor with granulocyte-colony stimulation factor (G-CSF) and the cells are harvested by apheresis for subsequent transplantation. After infusion in the recipient's bloodstream, the healthy hematopoietic cells migrate to the bone marrow where they can differentiate to yield mature blood cells and restore hematopoiesis. Recently plerixafor (MOZOBIL™, AMD3100, 1,1′-[1,4-phenylenebis (methylene)]-bis-1,4,8,11-tetraazacyclotetradecane) has been approved in combination with G-CSF to increase mobilization of progenitor cells in MM and NHL patients.
A significant limitation with the combinatory treatment with G-CSF and plerixafor is the slowness in stem cell mobilization. Although, experimental data in mice indicates a peak in mobilized stem cells following 1 hour after plerixafor administration (Broxmeyer 2005), the corresponding peak in humans starts first around 9 hours following plerixafor administration (Mozobil™ Product Monograph). Thereby, the harvest of mobilized stem cells is delayed until about 11 hours after the plerixafor administration, implying long hospitalization times (Mozobil™ Product Monograph). It is therefore the practice that plerixafor needs to be administered the day before the actual cell harvest.
Sweeney 2000 and Sweeney 2002 investigated the effects of sulfated polysaccharides, including 10 kDa dextran sulfate, in mobilization of stem/progenitor cells in mice and monkeys. In mice and monkeys dextran sulfate resulted in mobilization of colony forming cells (CFCs) following 3 hours and 6 hours, respectively, from dextran sulfate administration. The results presented in Sweeney 2000 and Sweeney 2002 therefore seem to indicate that dextran sulfate is about three times slower as compared to plerixafor in terms of mobilizing stem/progenitor cells.